The invention relates to the generation of droplets, in particular to be used for the production of freeze-dried pellets as bulkware, wherein a liquid feeding device is applied for the generation of droplets for the production of freeze-dried particles by means of a respective process line for droplet generation and freeze congealing of liquid droplets to form pellets.
The production method generally referred to as freeze-drying, also known as lyophilization, is a process for drying high-quality products such as, for example, pharmaceuticals, biotechnology materials such as proteins, enzymes, microorganisms, and in general any thermo- and/or hydrolysis-sensitive material. With freeze-drying, the frozen product is usually dried via the sublimation of ice crystals into water vapor, i.e. via the direct transition of water content from the solid phase into the gas phase. Freeze-drying is often performed under vacuum conditions but works generally also under atmospheric pressure.
Application examples for freeze-drying processes in the pharmaceutical area comprise drying drugs or APIs (Active Pharmaceutical Ingredients), API formulations, hormones, peptide-based hormones, monoclonal antibodies, blood plasma products or derivatives, vaccines or other injectables and in general substances which otherwise would not be stable over a required time span. Removing the water prior to sealing the product in vials or other appropriate containers for preserving sterility results in that the product can be stored and shipped, and permits that the product can later be reconstituted by dissolving the product in an appropriate medium, such as water or the like, prior to administration, e.g., by intradermal or intramuscular injection.
Design principles for freeze-dryer devices are well-known in the present technical field. For example, tray-based freeze-dryers comprise one or more trays or shelves within a (vacuum) drying chamber. Vials can be filled with the product and arranged on a tray, and then the tray with the filled vials is introduced into the freeze-dryer and the drying process is started.
Process systems combining spray-freezing and freeze-drying are also well-known in the present technical field. For instance, U.S. Pat. No. 3,601,901 describes a highly integrated device comprising a vacuum chamber with a freezing compartment and a drying compartment. The freezing compartment comprises a spray nozzle on top of an upwardly projecting portion of the vacuum chamber. The sprayed liquid is atomized and rapidly frozen into a number of small frozen particles which fall downwardly within the freezing compartment to arrive at a conveyor assembly. The conveyor advances the particles progressively for freeze-drying in the drying compartment. When the particles reach a discharge end of the conveyer, they are in freeze-dried form and fall downwardly into a discharge hopper.
As another example, WO 2005/105253 describes a freeze-drying apparatus for fruit juice, pharmaceuticals, nutraceuticals, tea, and coffee. A liquid substance is atomized through a high-pressure nozzle into a freezing chamber and reduced in temperature to below its eutectic temperature, thereby inducing a phase change of liquids in the liquid substance. A co-current flow of cold air freezes the droplets. The frozen droplets are then pneumatically conveyed by the cold air stream via a vacuum lock into a vacuum drying chamber and are further subjected to an energy source therein to assist sublimation of liquids as the substance is conveyed through the chamber.
Many products to be freeze-dried are compositions comprising two or more different input agents or components which are mixed prior to freeze-drying. Thus, a composition is mixed with a predefined ratio and is then freeze-dried and filled into vials for shipping. A change in the mixing ratio of the composition after filling into the vials is practically not feasible. The mixing, filling and drying processes therefore cannot normally be separated.
WO 2009/109550 A1 discloses a process for stabilizing an adjuvant containing a vaccine composition in dry form. It is proposed to separate if desirable the drying of the antigen from the drying of the adjuvant, followed by blending of the two before the filling or by sequential filling. Specifically, separate micropellets comprising either the antigen or the adjuvant are to be generated. The antigens micropellets and the adjuvants micropellets are then blended before filling into vials, or are directly filled to achieve the desired mixing ratio only at the time of blending or filling. Further it is possible to improve the overall stability, as the stabilizing formulations can be optimized independently for each component. The separated solid states allow to avoid interactions between the different components throughout storage, even at higher temperature.
Products such as to be found in the pharmaceutical or biotechnology area often have to be manufactured under closed conditions, i.e., they have to be manufactured under sterile conditions and/or under containment. Thus, a process line intended for a production under sterile conditions has to be adapted such that no impurities can enter and contaminate the product. Further, a process line adapted for a production under containment has to be adapted such that neither the product, elements thereof, nor auxiliary material can leave the process line and enter the environment. Here, one of the critical components for such a process line, in particular for the sterile manufacture of lyophilized microspheres, is the nozzle device serving to generate droplets to be freeze-dried, sometimes also referred to as spray nozzle or prilling nozzle. In particular, the nozzle can define in a very early stage of the process parameters of the product quality like particle size and particle size distribution. Due to this, the nozzle is a very important component of the bulk freeze drying process and a specific development area due to the number of parts of the nozzle, which are influencing the product quality significantly.
The detailed description of an example of such a prilling nozzle can be found in U.S. Pat. No. 6,458,296 B1, in which a nozzle is provided inside a reactor and consists of a carrier plate with a depression defined by a circular peripheral wall a bore extending from the center point of its bottom. The bore opens in a recess for accommodating a nozzle. Associated with the depression is a pressure ring fixing a diaphragm made of silicone and a seal, such that a pulsation chamber is provided by the diaphragm and the depression. The diaphragm carries a disk magnet which is fixed to the diaphragm, for example by gluing, and an electrical coil is suspended at a spacing with respect to the disk magnet, wherein alternating current flows passing through the coil generate alternately positive and negative magnetizations. The thus generated magnetic waves act on the disk magnet and cause it to vibrate together with the diaphragm, resulting in a resonant excitation of the same. In the pulsation chamber, a liquid is introduced and urged through the nozzle by the generated vibrations, leaving the nozzle in form of a liquid jet which breaks apart into droplets due to the surface tension, thereby generating ejected droplets, which is known as so called “laminar jet break up”. As long as no resonance frequency is initiated, the droplet size distribution is broad. The resonance frequency, however, leads to monosized droplets. Thereafter, the droplets pass through a central aperture of a metal ring connected to a high-voltage source, wherein the ejected droplets penetrate into an electrical field which is built up between the metal ring and the nozzle such that a charge flux occurs in the direction of the nozzle, providing the separated droplets with a similar electrostatic charge causing mutual repulsion of the droplets for separating the droplets from each other.
However, the solution as proposed in U.S. Pat. No. 6,458,296 B1 exhibits certain undesired disadvantages, such as a lack of suitability for CiP (“Cleaning in Place”) and/or SiP (“Sterilization in Place”) requirements, a weak fixing of the magnet on the diaphragm, leading to easy separation of the magnet, for example caused by heat, a high flexibility of the membrane resulting in the need to stabilize the membrane during sterilization, difficult mounting of the entire structure, a nozzle design intended for sterilization in an autoclave after disassembling the entire structure, no possibility of deaeration, i.e. gas-ventilation, without removing the nozzle, or sticking of the electrostatically charged droplets at the reactor walls or other components inside the reactor, resulting in undesired waste product. Therefore, there is a need for a redesigned prilling nozzle device resolving the cited disadvantages of the known prior art, focusing on improved reproducibility of droplet generation, improved design for CiP and SiP requirements, use of defined GMP (“Good Manufacturing Practice”) compatible materials, improved integration of droplet counting, and improved deflection system, i.e. preferably avoiding electrostatic charging that puts an impediment to further particle handling.
As further known prior art in regard to nozzle technique and droplet generation, EP 1 550 556 A1 describes a inkjet recording apparatus for jetting a droplet to a base member, wherein the apparatus comprises in some embodiments a liquid solution supplying section with a liquid solution chamber. Inside the chamber, a piezo element is arranged, and a driving voltage power source is provided for applying a driving voltage for changing the shape of the piezo element in order to achieve the jetting of a droplet to the outside of the chamber through a nozzle.
Now, in order to evaluate if a certain nozzle design provides useable nozzle functionality, droplets need to be identifiable over a distance of preferably 200 mm, wherein a variation of about 500 Hz should still be sufficient to provide droplets over the whole distance but of different droplet size, which indicates the robustness of the droplet formation by the respective nozzle design. The liquid feeding device of the present invention as described below fulfills these requirements.